Our initial studies have focused on patients who have undergone allogeneic hematopoietic stem cell transplantation (HSCT) as curative therapy primarily for hematological malignancies. More than 50% of HSCT recipients develop chronic Graft-Versus-Host-Disease (cGVHD), a multi-organ autoimmune-like disorder, and the oral cavity (oral mucosa or salivary glands) is affected in a majority of cGVHD patients. While mucosal manifestations are readily evaluable, pathologic changes in salivary glands progress silently from periductal and diffuse lymphocytic infiltrates to destruction of secretory acini and irreversible glandular fibrosis, with severe consequences on oral health, nutrition and quality of life. Understanding the mechanisms underlying salivary gland destruction may contribute to development of targeted therapies and non-invasive methods for serial screening and treatment of post-transplant patients prior to glandular destruction. We are investigating immune and physiologic causes of salivary gland dysfunction following allogeneic hematopoietic stem cell transplant using mouse and human models, and are conducting clinical trials directed toward advancing cGVHD therapy. Our recent work has identified immune cell populations in cGVHD-affected oral mucosa and salivary glands including CD4, CD8+T cells, regulatory and IL17-producing T cells. Analysis of the local biofluid of the oral cavity, saliva, shows close association between Th1 cytokines and chemokines and clinical disease severity in humans. Using immunohistochemistry, we have detected production of the interferon-induced GTPase protein MxA (myxoma resistance protein A) in human salivary glands and oral mucosa, providing direct evidence for active type 1 interferon signaling in cGVHD-affected oral tissues. In a mouse model of cGVHD, we have identified GVHD-like infiltration of lymphocytes in the salivary gland accompanied by structural alteration and fibrosis, suggesting that this system could be a powerful tool for mechanistic and interventional laboratory studies focused on cGVHD salivary gland pathogenesis. These studies are ongoing, and are contributing to a clear characterization of the pathogenic process of oral cGVHD in the salivary glands and oral mucosa that will lead to identification of additional therapeutic targets. Ongoing clinical trial work includes characterization and sampling of the oral cavity in patients following HSCT in conjunction with the NIH interdisciplinary cGVHD group. In summary, our current scientific investigation has identified specific immune cell populations active in the cGVHD salivary gland and supports their role in post-transplant tissue damage.